Topoisomerases are ubiquitous enzymes that participate in processes such as DNA replication, repair, transcription, and recombination as well as chromosome condensation and segregation. Topoisomerase I (TOP1) is the target of several antitumor agents based upon their ability to stabilize the enzyme-DNA cleavage complex, which results in DNA damage and ultimately cell death. Camptothecin (CPT) was the first compound identified as a TOP1-targeting agent (Hsaing, Y. H.; Hertsberg, R.; Hecht, S.; Liu, L. F. Camptothecin Induced Protein-Linked DNA Breaks Via Mammalian DNA Topoisomerase I, J. Biol. Chem., 1985, 260, 14873-14878). Two clinical TOP1-targeting agents, topotecan (Hycamtin®) and irinotecan (CPT-11/Camptosar®) have since been developed. The improved water-solubility of topotecan and irinotecan relative to CPT was critical to their development into the clinic. These agents have incorporated, within their structure, the core structure of camptothecin, which includes a δ-lactone. This lactone moiety is susceptible to hydrolysis and the resulting carboxylic acid has a high affinity for human serum albumin. In addition, it is known that both of these clinical agents are susceptible to transporter-mediated cellular efflux, which can limit intracellular accumulation and has been associated with multidrug resistance. Specifically overexpression of MDR1 (P-glycoprotein) and breast cancer resistance protein (BCRP) have been associated with resistance to these camptothecins.
Additional topoisomerase targeting agents with anticancer properties include those described by LaVoie et al. in U.S. Pat. No. 7,208,492. Particular compounds discussed include compound 206 and compound 216.
These are the compounds of formula II and formula I respectfully, as described in U.S. Pat. No. 7,208,492.
Despite these previous reports there is currently a need for additional agents that are useful for treating cancer. There is also a need for anticancer agents, particularly topoisomerase I targeting agents that have enhanced cytotoxicity or enhanced metabolic stability, prolonged half-lives or improved oral bioavailability in mammals, or for topoisomerase I targeting agents that are not substrates for an efflux transporter or that have a diminished ability to be removed from a cell by an efflux transporter.